Prosthetic tissue valves

ABSTRACT

A prosthetic valve comprising a plurality of ribbons comprising an extracellular matrix (ECM) composition, the proximal ends of the plurality of ribbons being positioned circumferentially and proximate each other, the distal ends of the plurality of ribbons also being positioned proximate each other, wherein a conical shaped valve member is formed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 14/960,354, filed on Dec. 5, 2015, which is acontinuation-in-part application of U.S. application Ser. No.14/229,854, filed on Mar. 29, 2014, now U.S. Pat. No. 9,308,084, whichclaims priority to U.S. Provisional Application No. 61/819,232, filed onMay 3, 2013.

FIELD OF THE INVENTION

The present invention generally relates to prosthetic valves forreplacing defective cardiovascular valves. More particularly, thepresent invention relates to prosthetic atrioventricular valves andmethods for anchoring same to cardiovascular structures and/or tissue.

BACKGROUND OF THE INVENTION

As is well known in the art, the human heart has four valves thatcontrol blood flow circulating through the human body. Referring toFIGS. 1A and 1B, on the left side of the heart 100 is the mitral valve102, located between the left atrium 104 and the left ventricle 106, andthe aortic valve 108, located between the left ventricle 106 and theaorta 110. Both of these valves direct oxygenated blood from the lungsinto the aorta 110 for distribution through the body.

The tricuspid valve 112, located between the right atrium 114 and theright ventricle 116, and the pulmonary valve 118, located between theright ventricle 116 and the pulmonary artery 120, however, are situatedon the right side of the heart 100 and direct deoxygenated blood fromthe body to the lungs.

Referring now to FIGS. 1C and 1D, there are also generally fivepapillary muscles in the heart 100; three in the right ventricle 116 andtwo in the left ventricle 106. The anterior, posterior and septalpapillary muscles 117 a, 117 b, 117 c of the right ventricle 116 eachattach via chordae tendinae 113 a, 113 b, 113 c to the tricuspid valve112. The anterior

and posterior papillary muscles 119 a, 119 b of the left ventricle 106attach via chordae tendinae 103 a, 103 b to the mitral valve 102 (seealso FIG. 1E).

Since heart valves are passive structures that simply open and close inresponse to differential pressures, the issues that can develop withvalves are typically classified into two categories: (i) stenosis, inwhich a valve does not open properly, and (ii) insufficiency (alsocalled regurgitation), in which a valve does not close properly.

Stenosis and insufficiency can occur as a result of severalabnormalities, including damage or severance of one or more chordeae.Stenosis and insufficiency can also occur concomitantly in the samevalve or in different valves.

Both of the noted valve abnormalities can adversely affect organfunction and result in heart failure. By way of example, referring firstto FIG. 1E, there is shown normal blood flow (denoted “BF_(N)”)proximate the mitral valve 102 during closure. Referring now to FIG. 1F,there is shown abnormal blood flow (denoted “BF_(A)”) or regurgitationcaused by a prolapsed mitral valve 102 p. As illustrated in FIG. 1F, theregurgitated blood “BF_(A)” flows back into the left atrium, which can,if severe, result in heart failure.

In addition to stenosis and insufficiency of a heart valve, surgicalintervention may also be required for certain types of bacterial orfungal infections, wherein the valve may continue to function normally,but nevertheless harbors an overgrowth of bacteria (i.e. “vegetation”)on the valve leaflets. The vegetation can, and in many instances will,flake off (i.e. “embolize”) and lodge downstream in a vital artery.

If such vegetation is present on the valves of the left side (i.e., thesystemic circulation side) of the heart, embolization can, and oftenwill, result in sudden loss of the blood supply to the affected bodyorgan and immediate malfunction of that organ. The organ most commonlyaffected by such embolization is the brain, in which case the patientcan, and in many instances will, suffer a stroke.

Likewise, bacterial or fungal vegetation on the tricuspid valve canembolize to the lungs. The noted embolization can, and in many instanceswill, result in lung dysfunction.

Treatment of the noted heart valve dysfunctions typically comprisesreparation of the diseased heart valve with preservation of thepatient's own valve or replacement of the valve with a mechanical orbioprosthetic valve, i.e. a prosthetic valve.

Various prosthetic heart valves have thus been developed for replacementof natural diseased or defective heart valves. Illustrative are thetubular prosthetic tissue valves disclosed in Applicant's U.S. Pat. Nos.9,044,319, 8,709,076 and 8,790,397, and Co-Pending U.S. application Ser.Nos. 13/560,573, 13/804,683, 13/480,347 and 13/480,324. A furthertubular prosthetic valve is disclosed in U.S. Pat. Nos. 8,257,434 and7,998,196.

Heart valve replacement requires a great deal of skill and concentrationto achieve a secure and reliable attachment of a prosthetic valve to acardiovascular structure or tissue. Various surgical methods forimplanting a prosthetic valve have thus been developed.

The most common surgical method that is employed to implant a prostheticvalve (mitral or tricuspid) comprises suturing a circular synthetic ringof a prosthetic valve to the annular tissue of the heart where adiseased valve has been removed.

A major problem associated with prosthetic valves is tissue valves withgluteraldehyde cross-linked leaflets will calcify and deteriorate overtime.

Another problem is mechanical valves will require anticoagulationagents, such as Coumadin, which can cause side effects in high doses,such as uncontrolled bleeding.

Another problem is the valves do not remodel into normal tissue capableof regeneration and self repair.

Another problem is many valves must be placed with open heart surgerywhile the patient is on a heart-lung machine.

There is thus a need to provide improved prosthetic tissue valves andmethods for attaching same to cardiovascular structures and/or tissuethat maintain or enhance the structural integrity of the valve whensubjected to cardiac cycle induced stress.

It is therefore an object of the present invention to provide improvedprosthetic tissue valves and methods for implanting same that overcomethe drawbacks and disadvantages associated with conventional prostheticatrioventricular valves.

It is another object of the present invention to provide improvedmethods for securely attaching prosthetic tissue valves tocardiovascular structures and/or tissue.

It is another object of the present invention to provide prosthetictissue valves having means for secure, reliable, and consistently highlyeffective attachment to cardiovascular structures and/or tissue.

It is another object of the present invention to provide extracellularmatrix (ECM) prosthetic tissue valves that induce host tissueproliferation, bioremodeling and regeneration of new tissue and tissuestructures with site-specific structural and functional properties.

It is another object of the present invention to provide ECM prosthetictissue valves that induce adaptive regeneration.

It is another object of the present invention to provide ECM prosthetictissue valves that are capable of administering a pharmacological agentto host tissue and, thereby produce a desired biological and/ortherapeutic effect.

SUMMARY OF THE INVENTION

The present invention is directed to prosthetic tissue valves that canbe readily employed to selectively replace diseased or defective heartvalves, and methods for attaching (or anchoring) same to cardiovascularstructures and/or tissue.

In some embodiments of the invention, the prosthetic tissue valvescomprise a plurality of continuous ribbon members configured to engage avalve annulus.

In a preferred embodiment, the proximal ends of the plurality of ribbonsare positioned circumferentially and proximate each other and the distalends of the plurality of ribbons are also being positioned proximateeach other, wherein the prosthetic tissue valves comprise asubstantially conical shape.

In some embodiments of the invention, the prosthetic tissue valvesfurther comprise a structural ring that is configured to receive andmaintain the distal ends of the ribbon members therein.

According to the invention, the ribbon members and structural ring cancomprise various biocompatible materials.

In some embodiments of the invention, the ribbon members and/orstructural ring preferably comprise an ECM composition comprisingacellular ECM derived from a mammalian tissue source.

In a preferred embodiment of the invention, the mammalian tissue sourceis selected from the group comprising small intestine submucosa (SIS),urinary bladder submucosa (UBS), stomach submucosa (SS), central nervoussystem tissue, mesodermal tissue, i.e. mesothelial tissue, dermalextracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, i.e. large and small intestines,tissue surrounding growing bone, placental extracellular matrix, omentumextracellular matrix, cardiac extracellular matrix, e.g., pericardiumand/or myocardium, kidney extracellular matrix, pancreas extracellularmatrix, lung extracellular matrix, and combinations thereof.

In some embodiments of the invention, the ECM composition comprises atleast one additional biologically active agent or composition, i.e. anagent that induces or modulates a physiological or biological process,or cellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

In some embodiments of the invention, the biologically active agentcomprises a growth factor, including, without limitation, transforminggrowth factor alpha (TGF-α), transforming growth factor beta (TGF-β),fibroblast growth factor-2 (FGF-2), and vascular epithelial growthfactor (VEGF).

In some embodiments of the invention, the ECM composition comprises atleast one pharmacological agent or composition (or drug), i.e. an agentor composition that is capable of producing a desired biological effectin vivo, e.g., stimulation or suppression of apoptosis, stimulation orsuppression of an immune response, etc.

In some embodiments of the invention, the pharmacological agentcomprises an anti-inflammatory agent.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawings, and in whichlike referenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIGS. 1A-1D are schematic illustrations of a human heart;

FIG. 1E is an illustration of a normal mitral valve;

FIG. 1F is an illustration of a prolapsed mitral valve;

FIG. 2 is a perspective view of one embodiment of a prosthetic tissuevalve, in accordance with the invention;

FIG. 3 is a side plane view of the prosthetic tissue valve shown in FIG.2, in accordance with the invention;

FIG. 4 is a perspective partial sectional view of another embodiment ofa prosthetic tissue valve shown in FIG. 2 having an annular ringdisposed at the proximal end of the valve, in accordance with theinvention;

FIG. 5 is a side plane view of the prosthetic tissue valve shown in FIG.4, in accordance with the invention;

FIG. 6 is an illustration of the prosthetic tissue valve shown in FIG. 4secured to the mitral valve annulus region and papillary muscles, inaccordance with the invention;

FIG. 7A is a perspective view of another embodiment of a prosthetictissue valve, in accordance with the invention;

FIG. 7B is an end plane view of the prosthetic tissue valve shown inFIG. 7A, in accordance with the invention;

FIG. 7C is a perspective partial sectional view of another embodiment ofa prosthetic tissue valve shown in FIG. 7A having an annular ringdisposed at the proximal end of the valve, in accordance with theinvention;

FIG. 7D is a perspective partial sectional view of yet anotherembodiment of a prosthetic tissue valve shown in FIG. 7A having anannular ring disposed at the proximal end of the valve and a structuralring disposed at the distal end of the valve, in accordance with theinvention;

FIG. 8A is a side plan view of another embodiment of a prosthetic tissuevalve in a pre-formed configuration, in accordance with the invention;

FIG. 8B is a perspective view of the prosthetic tissue valve shown inFIG. 8A in a formed configuration, in accordance with the invention;

FIG. 8C is a perspective partial sectional view of another embodiment ofa prosthetic tissue valve shown in FIG. 8B having an annular ringdisposed at the proximal end of the valve, in accordance with theinvention;

FIG. 8D is a perspective partial sectional view of yet anotherembodiment of a prosthetic tissue valve shown in FIG. 8B having anannular ring disposed at the proximal end of the valve and a structuralring disposed at the distal end of the valve, in accordance with theinvention;

FIG. 9 is an illustration of the prosthetic tissue valve shown in FIG.7C secured to the mitral valve annulus region, in accordance with theinvention;

FIG. 10 is an illustration of the prosthetic tissue valve shown in FIG.8C secured to the mitral valve annulus region, in accordance with theinvention;

FIG. 11 is an illustration of the prosthetic tissue valve shown in FIG.8B secured to the mitral valve annulus region, in accordance with theinvention;

FIG. 12 is a side plan view of one embodiment of a prosthetic tissuevalve ribbon member, in accordance with the invention;

FIG. 13 is a perspective view of yet another embodiment of a prosthetictissue valve comprising a plurality of the ribbon member shown in FIG.12, in accordance with the invention; and

FIG. 14 is an illustration of the prosthetic tissue valve shown in FIG.13 secured to the mitral valve annulus region, in accordance with theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified apparatus, systems, structures or methods as such may, ofcourse, vary. Thus, although a number of apparatus, systems and methodssimilar or equivalent to those described herein can be used in thepractice of the present invention, the preferred apparatus, systems,structures and methods are described herein.

It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments of the invention only andis not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one having ordinaryskill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein,whether supra or infra, are hereby incorporated by reference in theirentirety.

As used in this specification and the appended claims, the singularforms “a, “an” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to “apharmacological agent” includes two or more such agents and the like.

Further, ranges can be expressed herein as from “about” or“approximately” one particular value, and/or to “about” or“approximately” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about” or“approximately”, it will be understood that the particular value formsanother embodiment. It will be further understood that the endpoints ofeach of the ranges are significant both in relation to the otherendpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosedherein, and that each value is also herein disclosed as “about” or“approximately” that particular value in addition to the value itself.For example, if the value “10” is disclosed, then “approximately 10” isalso disclosed. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “10” is disclosed then “less than or equal to 10” as well as“greater than or equal to 10” is also disclosed.

Definitions

The terms “extracellular matrix”, “ECM”, and “ECM material” are usedinterchangeably herein, and mean and include a collagen-rich substancethat is found in between cells in mammalian tissue, and any materialprocessed therefrom, e.g. decellularized ECM. According to theinvention, ECM can be derived from a variety of mammalian tissuesources, including, without limitation, small intestine submucosa (SIS),urinary bladder submucosa (UBS), stomach submucosa (SS), central nervoussystem tissue, epithelium of mesodermal origin, i.e. mesothelial tissue,dermal extracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, i.e. large and small intestines,tissue surrounding growing bone, placental extracellular matrix, omentumextracellular matrix, cardiac extracellular matrix, e.g., pericardiumand/or myocardium, kidney extracellular matrix, pancreas extracellularmatrix, lung extracellular matrix, and combinations thereof. The ECMmaterial can also comprise collagen from mammalian sources.

The term “acellular ECM”, as used herein, means and includes ECM thathas a reduced content of cells, i.e. decellularized ECM.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa(SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/orSIS and/or SS material that includes the tunica mucosa (which includesthe transitional epithelial layer and the tunica propria), submucosallayer, one or more layers of muscularis, and adventitia (a looseconnective tissue layer) associated therewith.

ECM can also be derived from basement membrane of mammaliantissue/organs, including, without limitation, urinary basement membrane(UBM), liver basement membrane (LBM), and amnion, chorion, allograftpericardium, allograft acellular dermis, amniotic membrane, Wharton'sjelly, and combinations thereof.

Additional sources of mammalian basement membrane include, withoutlimitation, spleen, lymph nodes, salivary glands, prostate, pancreas andother secreting glands.

According to the invention, the ECM can be derived from xenogeneic andallogeneic tissue sources.

ECM can also be derived from other sources, including, withoutlimitation, collagen from plant sources and synthesized extracellularmatrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic processinvolving the growth of new blood vessels from pre-existing bloodvessels.

The term “neovascularization”, as used herein, means and includes theformation of functional vascular networks that can be perfused by bloodor blood components. Neovascularization includes angiogenesis, buddingangiogenesis, intussuceptive angiogenesis, sprouting angiogenesis,therapeutic angiogenesis and vasculogenesis.

The term “biologically active agent”, as used herein, means and includesagent that induces or modulates a physiological or biological process,or cellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

The term “biologically active agent” thus means and includes, withoutlimitation, the following growth factors: platelet derived growth factor(PDGF), epidermal growth factor (EGF), transforming growth factor alpha(TGF-α), transforming growth factor beta (TGF-β), fibroblast growthfactor-2 (FGF-2), vascular epithelial growth factor (VEGF), hepatocytegrowth factor (HGF), insulin-like growth factor (IGF), nerve growthfactor (NGF), platelet derived growth factor (PDGF), tumor necrosisfactor alpha (TNA-alpha), and placental growth factor (PLGF).

The term “biologically active agent” also means and includes, withoutlimitation, human embryonic stem cells, fetal cardiomyocytes,myofibroblasts, mesenchymal stem cells, autotransplated expandedcardiomyocytes, adipocytes, totipotent cells, pluripotent cells, bloodstem cells, myoblasts, adult stem cells, bone marrow cells, mesenchymalcells, embryonic stem cells, parenchymal cells, epithelial cells,endothelial cells, mesothelial cells, fibroblasts, osteoblasts,chondrocytes, exogenous cells, endogenous cells, stem cells,hematopoietic stem cells, bone-marrow derived progenitor cells,myocardial cells, skeletal cells, fetal cells, undifferentiated cells,multi-potent progenitor cells, unipotent progenitor cells, monocytes,cardiac myoblasts, skeletal myoblasts, macrophages, capillaryendothelial cells, xenogeneic cells, allogeneic cells, and post-natalstem cells.

The term “biologically active agent” also means and includes, withoutlimitation, the following biologically active agents (referred tointerchangeably herein as a “protein”, “peptide” and “polypeptide”):collagen (types I-V), proteoglycans, glycosaminoglycans (GAGs),glycoproteins, growth factors, cytokines, cell-surface associatedproteins, cell adhesion molecules (CAM), angiogenic growth factors,endothelial ligands, matrikines, cadherins, immuoglobins, fibrilcollagens, non-fibrallar collagens, basement membrane collagens,multiplexins, small-leucine rich proteoglycans, decorins, biglycans,fibromodulins, keratocans, lumicans, epiphycans, heparin sulfateproteoglycans, perlecans, agrins, testicans, syndecans, glypicans,serglycins, selectins, lecticans, aggrecans, versicans, neurocans,brevicans, cytoplasmic domain-44 (CD-44), macrophage stimulatingfactors, amyloid precursor proteins, heparins, chondroitin sulfate B(dennatan sulfate), chondroitin sulfate A, heparin sulfates, hyaluronicacids, fibronectins, tenascins, elastins, fibrillins, laminins,nidogen/enactins, fibulin I, fibulin II, integrins, transmembranemolecules, thrombospondins, osteopontins, and angiotensin convertingenzymes (ACE).

The term “biologically active composition”, as used herein, means andincludes a composition comprising a “biologically active agent”.

The terms “pharmacological agent”, “active agent” and “drug” are usedinterchangeably herein, and mean and include an agent, drug, compound,composition of matter or mixture thereof, including its formulation,which provides some therapeutic, often beneficial, effect. This includesany physiologically or pharmacologically active substance that producesa localized or systemic effect or effects in animals, including warmblooded mammals, humans and primates; avians; domestic household or farmanimals, such as cats, dogs, sheep, goats, cattle, horses and pigs;laboratory animals, such as mice, rats and guinea pigs; fish; reptiles;zoo and wild animals; and the like.

The terms “pharmacological agent”, “active agent” and “drug” thus meanand include, without limitation, antibiotics, anti-arrhythmic agents,anti-viral agents, analgesics, steroidal anti-inflammatories,non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics,modulators of cell-extracellular matrix interactions, proteins,hormones, growth factors, matrix metalloproteinases (MMPs), enzymes andenzyme inhibitors, anticoagulants and/or antithrombotic agents, DNA,RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or proteinsynthesis, polypeptides, oligonucleotides, polynucleotides,nucleoproteins, compounds modulating cell migration, compoundsmodulating proliferation and growth of tissue, and vasodilating agents.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include, without limitation, atropine, tropicamide, dexamethasone,dexamethasone phosphate, betamethasone, betamethasone phosphate,prednisolone, triamcinolone, triamcinolone acetonide, fluocinoloneacetonide, anecortave acetate, budesonide, cyclosporine, FK-506,rapamycin, ruboxistaurin, midostaurin, flurbiprofen, suprofen,ketoprofen, diclofenac, ketorolac, nepafenac, lidocaine, neomycin,polymyxin b, bacitracin, gramicidin, gentamicin, oyxtetracycline,ciprofloxacin, ofloxacin, tobramycin, amikacin, vancomycin, cefazolin,ticarcillin, chloramphenicol, miconazole, itraconazole, trifluridine,vidarabine, ganciclovir, acyclovir, cidofovir, ara-amp, foscarnet,idoxuridine, adefovir dipivoxil, methotrexate, carboplatin,phenylephrine, epinephrine, dipivefrin, timolol, 6-hydroxydopamine,betaxolol, pilocarpine, carbachol, physostigmine, demecarium,dorzolamide, brinzolamide, latanoprost, sodium hyaluronate, insulin,verteporfin, pegaptanib, ranibizumab, and other antibodies,antineoplastics, anti-VEGFs, ciliary neurotrophic factor, brain-derivedneurotrophic factor, bFGF, Caspase-1 inhibitors, Caspase-3 inhibitors,α-Adrenoceptors agonists, NMDA antagonists, Glial cell line-derivedneurotrophic factors (GDNF), pigment epithelium-derived factor (PEDF),and NT-3, NT-4, NGF, IGF-2.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include the following Class I-Class V antiarrhythmic agents: (ClassIa) quinidine, procainamide and disopyramide; (Class Ib) lidocaine,phenytoin and mexiletine; (Class Ic) flecainide, propafenone andmoricizine; (Class II) propranolol, esmolol, timolol, metoprolol andatenolol; (Class III) amiodarone, sotalol, ibutilide and dofetilide;(Class IV) verapamil and diltiazem) and (Class V) adenosine and digoxin.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include, without limitation, the following antiobiotics:aminoglycosides, cephalosporins, chloramphenicol, clindamycin,erythromycins, fluoroquinolones, macrolides, azolides, metronidazole,penicillins, tetracyclines, trimethoprim-sulfamethoxazole andvancomycin.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include, without limitation, the following steroids: andranes (e.g.,testosterone), cholestanes, cholic acids, corticosteroids (e.g.,dexamethasone), estraenes (e.g., estradiol) and pregnanes (e.g.,progesterone).

The terms “pharmacological agent”, “active agent” and “drug” also meanand include one or more classes of narcotic analgesics, including,without limitation, morphine, codeine, heroin, hydromorphone,levorphanol, meperidine, methadone, oxycodone, propoxyphene, fentanyl,methadone, naloxone, buprenorphine, butorphanol, nalbuphine andpentazocine.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include one or more classes of topical or local anesthetics,including, without limitation, esters, such as benzocaine,chloroprocaine, cocaine, cyclomethycaine, dimethocaine/larocaine,piperocaine, propoxycaine, procaine/novacaine, proparacaine, andtetracaine/amethocaine. Local anesthetics can also include, withoutlimitation, amides, such as articaine, bupivacaine,cinchocaine/dibucaine, etidocaine, levobupivacaine,lidocaine/lignocaine, mepivacaine, prilocaine, ropivacaine, andtrimecaine. Local anesthetics can further include combinations of theabove from either amides or esters.

As indicated above, the terms “pharmacological agent”, “active agent”and “drug” also mean and include an anti-inflammatory.

The terms “anti-inflammatory” and “anti-inflammatory agent” are alsoused interchangeably herein, and mean and include a “pharmacologicalagent” and/or “active agent formulation”, which, when a therapeuticallyeffective amount is administered to a subject, prevents or treats bodilytissue inflammation i.e. the protective tissue response to injury ordestruction of tissues, which serves to destroy, dilute, or wall offboth the injurious agent and the injured tissues.

Anti-inflammatory agents thus include, without limitation, alclofenac,alclometasone dipropionate, algestone acetonide, alpha amylase,amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride,anakinra, anirolac, anitrazafen, apazone, balsalazide disodium,bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, decanoate, deflazacort,delatestryl, depo-testosterone, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, mesterolone,methandrostenolone, methenolone, methenolone acetate, methylprednisolonesuieptanate, momiflumate, nabumetone, nandrolone, naproxen, naproxensodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin,oxandrolane, oxaprozin, oxyphenbutazone, oxymetholone, paranylinehydrochloride, pentosan polysulfate sodium, phenbutazone sodiumglycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,stanozolol, sudoxicam, sulindac, suprofen, talmetacin, talniflumate,talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam,tesimide, testosterone, testosterone blends, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, and zomepirac sodium.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include a statin, i.e. a HMG-CoA reductase inhibitor, including,without limitation, atorvastatin (Lipitor®), cerivastatin, fluvastatin(Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), mevastatin,pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine®,Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®).

The term “pharmacological composition”, as used herein, means andincludes a composition comprising a “pharmacological agent” and/or anyadditional agent or component identified herein.

The term “therapeutically effective”, as used herein, means that theamount of the “pharmacological agent” and/or “biologically active agent”and/or “pharmacological composition” and/or “biologically activecomposition” administered is of sufficient quantity to ameliorate one ormore causes, symptoms, or sequelae of a disease or disorder. Suchamelioration only requires a reduction or alteration, not necessarilyelimination, of the cause, symptom, or sequelae of a disease ordisorder.

The terms “patient” and “subject” are used interchangeably herein, andmean and include warm blooded mammals, humans and primates; avians;domestic household or farm animals, such as cats, dogs, sheep, goats,cattle, horses and pigs; laboratory animals, such as mice, rats andguinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the term, such as “comprising” and“comprises,” means “including, but not limited to” and is not intendedto exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enablingfashion the best modes of performing one or more embodiments of thepresent invention. The disclosure is further offered to enhance anunderstanding and appreciation for the inventive principles andadvantages thereof, rather than to limit in any manner the invention.The invention is defined solely by the appended claims including anyamendments made during the pendency of this application and allequivalents of those claims as issued.

As stated above, the present invention is directed to prosthetic tissuevalves that can be readily employed to selectively replace diseased ordefective valves in the heart, and methods for attaching (or anchoring)same to cardiovascular structures and/or tissue.

As discussed in detail below, in some embodiments of the invention, theprosthetic tissue valves comprise continuous tubular members.

In some embodiments, the proximal end of the tubular members comprise anannular ring that is designed and configured to securely engage thetubular members and, hence, prosthetic tissue valves formed therefrom toa valve annulus and, hence, cardiovascular tissue associated therewith.

In some embodiments of the invention, the prosthetic valves comprisecontinuous conical shaped structural members.

In some embodiments, the conical shaped structural members and, hence,prosthetic tissue valves formed therefrom, similarly comprise an annularring that is designed and configured to securely engage the conicalshaped structural members and, hence, prosthetic tissue valves formedtherefrom to a valve annulus and, hence, cardiovascular tissueassociated therewith.

In some embodiments of the invention, the distal end of the conicalshaped structural members and, hence, prosthetic tissue valves formedtherefrom, comprises a structural ring.

In some embodiments of the invention, the prosthetic tissue valvescomprise a plurality of ribbon members.

According to the invention, the tubular members, conical shaped membersand ribbon members can comprise various biocompatible materials andcompositions formed therefrom.

In some embodiments of the invention, the tubular shaped members,conical shaped members and ribbon members comprise sheet members.

According to the invention, the tubular shaped sheet members conicalshaped members and ribbon members can comprise single or multi-sheetmembers.

According to the invention, the sheet(s) can be formed into the tubularand conical shaped members of the invention and secured about the matingedges by various conventional means, e.g., suturing the mating edgestogether.

In some embodiments of the invention, the tubular shaped members and/orannular ring comprise ECM derived from a mammalian tissue source.

In some embodiments of the invention, the conical shaped members and/orribbon members and/or annular ring and/or structural ring similarlycomprise ECM derived from a mammalian tissue source.

In a preferred embodiment of the invention, the ECM comprises acellularECM.

As discussed in detail herein, it is contemplated that, followingplacement of a prosthetic tissue valve comprising an ECM composition,e.g., a conical shaped member or prosthetic tissue valve comprising aplurality of ribbon members comprising an ECM composition, (hereinafter“an ECM prosthetic tissue valve”) on a cardiovascular structure (orstructures) in a subject, e.g. valve annulus, and, hence, cardiovasculartissue associated therewith, the ECM prosthetic tissue valve will induce“modulated healing” of the cardiovascular structure(s) and tissueassociated therewith.

As discussed in detail herein, it is contemplated that, followingplacement of an ECM prosthetic tissue valve on a cardiovascularstructure (or structures) in a subject, the ECM prosthetic tissue valvewill become populated with cells from the subject that will graduallyremodel the ECM into cardiovascular tissue and tissue (and, hence,valve) structures.

It is further contemplated that, following placement of an ECMprosthetic tissue valve on a cardiovascular structure (or structures) ina subject, stem cells will migrate to the ECM prosthetic tissue valvefrom the point(s) at which the valve is attached to the cardiovascularstructure, e.g., valve annulus, or structures, e.g., valve annulus andheart wall.

It is still further contemplated that the points at which an ECMprosthetic tissue valve is attached to a cardiovascular structure (orstructures) in a subject will serve as points of constraint that directthe remodeling of the ECM into cardiovascular tissue and valvestructures that are identical or substantially identical to properlyfunctioning native cardiovascular tissue and valve structures.

It is still further contemplated that, during circulation of epithelialand endothelial progenitor cells after placement of an ECM prosthetictissue valve on a cardiovascular structure (or structures), the surfacesof an ECM prosthetic tissue valve will rapidly become lined or coveredwith epithelial and/or endothelial progenitor cells.

As indicated above, in some embodiments of the invention, the proximalends of prosthetic tissue valves of the invention comprise an annularring that is designed and configured to securely engage the prosthetictissue valves to a valve annulus (and, hence, cardiovascular tissueassociated therewith).

In some embodiments of the invention, the annular ring comprises atleast one anchoring mechanism that is configured to position theprosthetic tissue valves proximate a valve annulus, and maintain contacttherewith for a pre-determined anchor support time period. According tothe invention, the anchoring mechanisms can comprise various forms andmaterials, such as disclosed in U.S. Pat. No. 9,044,319, which isincorporated by reference herein in its entirety.

In some embodiments of the invention, the anchoring mechanisms areconfigured to position ECM prosthetic tissue valves of the inventionproximate a valve annulus, and maintain contact therewith for apredetermined temporary anchor support period of time within the processof tissue regeneration.

As also indicated above, in some embodiments, the distal end ofprosthetic tissue valves comprising a conical shaped structural memberor a plurality of ribbon members further comprise a structural ring.

According to the invention, the annular ring and structural ring canalso comprise various biocompatible materials and compositions formedtherefrom. Suitable biocompatible ring materials are disclosed inCo-Pending U.S. application Ser. No. 14/953,548, which is incorporatedby reference herein.

In some embodiments of the invention, the annular ring and/or structuralring comprise a polymeric composition comprising a biodegradablepolymeric material. According to the invention, suitable biodegradablepolymeric materials comprise, without limitation, polycaprolactone(PCL), Artelon® (porous polyurethaneurea), polyglycolide (PGA),polylactide (PLA), poly(ε-caprolactone) (PCL), poly dioxanone (apolyether-ester), poly lactide-co-glycolide, polyamide esters,polyalkalene esters, polyvinyl esters, polyvinyl alcohol, andpolyanhydrides.

According to the invention, the polymeric composition can furthercomprise a natural polymer, including, without limitation,polysaccharides (e.g. starch and cellulose), proteins (e.g., gelatin,casein, silk, wool, etc.), and polyesters (e.g., polyhydroxyalkanoates).

The polymeric composition can also comprise a hydrogel composition,including, without limitation, polyurethane, poly(ethylene glycol),poly(propylene glycol), poly(vinylpyrrolidone), xanthan, methylcellulose, carboxymethyl cellulose, alginate, hyaluronan, poly(acrylicacid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl cellulose,methacrylic acid, αβ-glycerophosphate, κ-carrageenan,2-acrylamido-2-methylpropanesulfonic acid, and β-hairpin peptide.

According to the invention, the polymeric composition can furthercomprise a non-biodegradable polymer, including, without limitation,polytetrafluoro ethylene (Teflon®) and polyethylene terephthalate(Dacron®).

In some embodiments of the invention, the polymeric compositioncomprises poly(urethane urea); preferably, Artelon® distributed byArtimplant AB in Goteborg, Sweden.

In some embodiments, the polymeric composition comprises poly(glycerolsebacate) (PGS).

In some embodiments of the invention, annular ring and/or structuralring comprise a biocompatible metal. According to the invention,suitable metals comprise, without limitation, Nitinol®, stainless steeland magnesium.

In a preferred embodiment of the invention, the tubular shaped memberscomprise an ECM composition comprising ECM derived from a mammaliantissue source.

In a preferred embodiment, the conical shaped structural membersimilarly comprises an ECM composition comprising ECM derived from amammalian tissue source.

In a preferred embodiment, the ribbon members similarly comprise an ECMcomposition comprising ECM derived from a mammalian tissue source.

In some embodiments, the annular ring and/or structural ring alsopreferably comprise an ECM composition comprising acellular ECM derivedfrom a mammalian tissue source.

According to the invention, the ECM can be derived from variousmammalian tissue sources and methods for preparing same, such asdisclosed in U.S. Pat. Nos. 7,550,004, 7,244,444, 6,379,710, 6,358,284,6,206,931, 5,733,337 and 4,902,508 and U.S. application Ser. No.12/707,427; which are incorporated by reference herein in theirentirety.

The mammalian tissue sources include, without limitation, the smallintestine, large intestine, stomach, lung, liver, kidney, pancreas,peritoneum, placenta, heart, bladder, prostate, tissue surroundinggrowing enamel, tissue surrounding growing bone, and any fetal tissuefrom any mammalian organ.

The mammalian tissue can thus comprise, without limitation, smallintestine submucosa (SIS), urinary bladder submucosa (UBS), stomachsubmucosa (SS), central nervous system tissue, epithelium of mesodermalorigin, i.e. mesothelial tissue, dermal extracellular matrix,subcutaneous extracellular matrix, gastrointestinal extracellularmatrix, i.e. large and small intestines, tissue surrounding growingbone, placental extracellular matrix, omentum extracellular matrix,cardiac extracellular matrix, e.g., pericardium and/or myocardium,kidney extracellular matrix, pancreas extracellular matrix, lungextracellular matrix, and combinations thereof. The ECM can alsocomprise collagen from mammalian sources.

In some embodiments of the invention, the mammalian tissue sourcecomprises mesothelial tissue.

In some embodiments, the mammalian tissue source comprises an adolescentmammalian tissue source, e.g. tissue derived from a porcine mammal lessthan 3 years of age.

According to the invention, the ECM can also be derived from the same ordifferent mammalian tissue sources, as disclosed in Co-Pendingapplication Ser. Nos. 13/033,053 and 13/033,102; which are incorporatedby reference herein.

In a preferred embodiment of the invention, the ECM comprises sterilizedand decellularized (or acellular) ECM.

According to the invention, the ECM can be sterilized and decellularizedby various conventional means.

In some embodiments of the invention, the ECM is sterilized anddecellularized via applicant's proprietary process disclosed inCo-Pending U.S. application Ser. No. 13/480,205; which is expresslyincorporated by reference herein in its entirety.

In some embodiments of the invention, the ECM comprises crosslinked ECM.According to the invention, the ECM can be crosslinked by variousconventional materials and methods.

As stated above, in some embodiments of the invention, the ECMcomposition (and, hence, tubular shaped members and/or conical shapedstructural members and/or ribbon members and/or annular ring and/orstructural ring formed therefrom) further comprises at least oneadditional biologically active agent or composition, i.e. an agent thatinduces or modulates a physiological or biological process, or cellularactivity, e.g., induces proliferation, and/or growth and/or regenerationof tissue.

According to the invention, suitable biologically active agents includeany of the aforementioned biologically active agents, including, withoutlimitation, the aforementioned growth factors, cells and proteins.

In some embodiments of the invention, the ECM composition (and, hence,tubular shaped members and/or conical shaped structural members and/orribbon members and/or annular ring and/or structural ring formedtherefrom) further comprises at least one pharmacological agent orcomposition (or drug), i.e. an agent or composition that is capable ofproducing a desired biological effect in vivo, e.g., stimulation orsuppression of apoptosis, stimulation or suppression of an immuneresponse, etc.

According to the invention, suitable pharmacological agents andcompositions include any of the aforementioned agents, including,without limitation, antibiotics, anti-viral agents, analgesics,steroidal anti-inflammatories, non-steroidal anti-inflammatories,anti-neoplastics, anti-spasmodics, modulators of cell-extracellularmatrix interactions, proteins, hormones, enzymes and enzyme inhibitors,anticoagulants and/or antithrombotic agents, DNA, RNA, modified DNA andRNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides,oligonucleotides, polynucleotides, nucleoproteins, compounds modulatingcell migration, compounds modulating proliferation and growth of tissue,and vasodilating agents.

In some embodiments of the invention, the pharmacological agentcomprises an anti-inflammatory agent.

In some embodiments, the pharmacological agent comprises a statin, i.e.a HMG-CoA reductase inhibitor. According to an aspect of the invention,suitable statins include, without limitation, atorvastatin (Lipitor®),cerivastatin, fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®,Altoprev®), mevastatin, pitavastatin (Livalo®, Pitava®), pravastatin(Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®), andsimvastatin (Zocor®, Lipex®). Several actives comprising a combinationof a statin and another agent, such as ezetimbe/simvastatin (Vytorin®),are also suitable.

It has been found that the noted statins exhibit numerous beneficialproperties that provide several beneficial biochemical actions oractivities in vivo; particularly, when the statins are a component of anECM composition comprising acellular ECM, i.e. a statin augmented ECMcomposition. The properties and beneficial actions are set forth inApplicant's U.S. Pat. No. 9,072,816 and Co-Pending application Ser. No.13/782,024, filed on Mar. 1, 2013 and Ser. No. 14/554,730, filed on Nov.26, 2014; which are incorporated by reference herein in their entirety.

In some embodiments of the invention, the pharmacological agentcomprises chitosan. As also set forth in detail in U.S. Pat. No.9,072,816, chitosan similarly exhibits numerous beneficial propertiesthat provide several beneficial biochemical actions or activities invivo; particularly when chitosan is a component of an ECM compositioncomprising acellular ECM.

As indicated above, it is contemplated that, following placement of anECM prosthetic tissue valve, i.e. a prosthetic tissue valve comprisingan ECM composition, on a cardiovascular structure (or structures) in asubject, e.g. valve annulus, and, hence, cardiovascular tissueassociated therewith, the ECM prosthetic tissue valve will induce“modulated healing” of the cardiovascular structure(s) andcardiovascular tissue associated therewith.

The term “modulated healing”, as used herein, and variants of thislanguage generally refer to the modulation (e.g., alteration, delay,retardation, reduction, etc.) of a process involving different cascadesor sequences of naturally occurring tissue repair in response tolocalized tissue damage or injury, substantially reducing theirinflammatory effect. Modulated healing, as used herein, includes manydifferent biologic processes, including epithelial growth, fibrindeposition, platelet activation and attachment, inhibition,proliferation and/or differentiation, connective fibrous tissueproduction and function, angiogenesis, and several stages of acuteand/or chronic inflammation, and their interplay with each other.

For example, in some embodiments of the invention, the ECM prosthetictissue valves of the invention are specifically formulated (or designed)to alter, delay, retard, reduce, and/or detain one or more of the phasesassociated with healing of damaged tissue, including, but not limitedto, the inflammatory phase (e.g., platelet or fibrin deposition), andthe proliferative phase when in contact with biological tissue.

In some embodiments, “modulated healing” means and includes the abilityof an ECM prosthetic tissue valve of the invention to restrict theexpression of inflammatory components. By way of example, according tothe invention, when a tubular member or conical shaped member (and/orannular ring and/or structural ring) of a prosthetic tissue valvecomprises a statin augmented ECM composition, i.e. a compositioncomprising ECM and a statin, and the ECM prosthetic tissue valve ispositioned proximate damaged biological tissue, e.g., attached to avalve annulus, the ECM prosthetic tissue valve restricts expression ofmonocyte chemoattractant protein-1 (MCP-1) and chemokine (C-C) motifligand 2 (CCR2).

In some embodiments of the invention, “modulated healing” means andincludes the ability of an ECM prosthetic tissue valve of the inventionto alter a substantial inflammatory phase (e.g., platelet or fibrindeposition) at the beginning of the tissue healing process. As usedherein, the phrase “alter a substantial inflammatory phase” refers tothe ability of a prosthetic tissue valve of the invention tosubstantially reduce the inflammatory response at a damaged tissue site,e.g. valve annulus, when in contact with tissue at the site.

In such an instance, a minor amount of inflammation may ensue inresponse to tissue injury, but this level of inflammation response,e.g., platelet and/or fibrin deposition, is substantially reduced whencompared to inflammation that takes place in the absence of an ECMprosthetic tissue valve of the invention.

The term “modulated healing” also refers to the ability of an ECMprosthetic tissue valve of the invention to induce host tissueproliferation, bioremodeling, including neovascularization, e.g.,vasculogenesis, angiogenesis, and intussusception, and regeneration oftissue structures with site-specific structural and functionalproperties, when disposed proximate damaged tissue, e.g. valve annulus.

Thus, in some embodiments of the invention, the term “modulated healing”means and includes the ability of an ECM prosthetic tissue valve of theinvention to modulate inflammation and induce host tissue proliferationand remodeling, when disposed proximate damaged tissue.

It is further contemplated that, during a cardiac cycle after placementof an ECM prosthetic tissue valve on a valve structure or structures,wherein the ECM prosthetic tissue valve is subjected to physicalstimuli, adaptive regeneration of the prosthetic tissue valve is alsoinduced.

By the term “adaptive regeneration,” it is meant to mean the process ofinducing modulated healing of damaged tissue concomitantly withstress-induced hypertrophy of an ECM prosthetic tissue valve of theinvention, wherein the ECM prosthetic tissue valve adaptively remodelsand forms functioning valve structures that are substantially identicalto native valve structures.

As indicated above, it is further contemplated that the points at whichan ECM prosthetic tissue valve is attached to a cardiovascular structure(or structures) in a subject will serve as points of constraint thatdirect the remodeling of the ECM into cardiovascular tissue and valvestructures that are substantially identical to properly functioningnative cardiovascular tissue and valve structures.

Referring now to FIGS. 2-5, two (2) embodiments of a prosthetic tissuevalve of the invention will be described in detail.

Referring first to FIGS. 2 and 3, in one embodiment of the invention,the prosthetic tissue valve 10 a comprises a continuous tubular member12 having first or “proximal” and second or “distal” ends 14, 16. Insome embodiments of the invention, the valve 10 a further comprises atleast one internal leaflet, such as disclosed in U.S. Pat. No. 8,709,076and Co-Pending U.S. application Ser. No. 13/804,683, which areincorporated by reference herein.

In some embodiments, the tubular member 12 comprises a leaflet forminginterior surface, such as disclosed in Co-Pending U.S. application Ser.Nos. 13/480,324 and 13/480,347, which are similarly incorporated byreference herein.

According to the invention, the tubular member 12 can comprise variousbiocompatible materials, including, without limitation, mammaliantissue, e.g., bovine tissue.

In some embodiments of the invention, the tubular member 12 comprises abiocompatible polymeric material. According to the invention, suitablepolymeric materials comprise Dacron®, polyether ether ketone (PEEK), andlike materials.

As indicated above, in some embodiments, the tubular member 12 comprisesan ECM composition comprising ECM derived a mammalian tissue source.According to the invention, the ECM can be derived from variousmammalian tissue sources including, without limitation, small intestinesubmucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa(SS), central nervous system tissue, mesodermal origin, i.e. mesothelialtissue, dermal extracellular matrix, subcutaneous extracellular matrix,gastrointestinal extracellular matrix, i.e. large and small intestines,tissue surrounding growing bone, placental extracellular matrix, omentumextracellular matrix, cardiac extracellular matrix, e.g., pericardiumand/or myocardium, kidney extracellular matrix, pancreas extracellularmatrix, lung extracellular matrix, and combinations thereof.

According to the invention, the ECM can also comprise collagen frommammalian sources.

As also indicated above, the ECM preferably comprises acellular ECM.

In some embodiments of the invention, the ECM composition and, hence,tubular member 12 formed therefrom, further comprises at least oneadditional biologically active agent or composition, i.e. an agent thatinduces or modulates a physiological or biological process, or cellularactivity, e.g., induces proliferation, and/or growth and/or regenerationof tissue.

According to the invention, suitable biologically active agents includeany of the aforementioned biologically active agents.

In some embodiments of the invention, the ECM composition and, hence,tubular member 12 formed therefrom, further comprises at least onepharmacological agent or composition (or drug), i.e. an agent orcomposition that is capable of producing a desired biological effect invivo, e.g., stimulation or suppression of apoptosis, stimulation orsuppression of an immune response, etc.

According to the invention, suitable pharmacological agents andcompositions include any of the aforementioned agents, including,without limitation, antibiotics and anti-inflammatories.

In a preferred embodiment of the invention, the distal end 16 of thetubular member 12 includes cardiovascular structure engagement means 18that is designed and configured to securely engage the member 12 and,hence, prosthetic tissue valve 10 a formed therefrom, to cardiovascularstructures, such as selective papillary muscles and/or cardiovasculartissue.

As illustrated in FIGS. 2 and 3, in some embodiments of the invention,the cardiovascular structure engagement means 18 comprises a pair ofvalve leaflet extensions 22 a, 22 b, which, in some embodiments of theinvention, extend from a valve leaflet to mimic the chordae tendineae.According to the invention, the valve leaflet extensions 22 a, 22 b canbe disposed at various positions about the periphery of the distal end16 of the tubular member 12.

In some embodiments of the invention, wherein the prosthetic tissuevalve 10 a is employed to replace a mitral valve, the leaflet extensions22 a, 22 b are preferably spaced at approximately 0° and 120° about theperiphery of the distal end 16 of the tubular member 12.

According to the invention, the valve leaflet extensions 22 a, 22 b canalso have various predetermined lengths to accommodate attachment todesired cardiovascular structures, e.g., selective papillary muscles.

The valve leaflet extensions 22 a, 22 b can also comprise the samematerial as the tubular member 12 or a different material, e.g. tubularmember 12 comprises SIS and the valve leaflet extensions 22 a, 22 bcomprise a polymeric material.

Referring now to FIGS. 4 and, 5, in a further embodiment of theinvention, the prosthetic tissue valve 10 a shown in FIGS. 2 and 3further comprises an annular ring 15 that is disposed on the proximalend 14 of the valve 10 a, forming valve 10 b. As indicated above,suitable annular rings and ring materials are disclosed in Co-PendingU.S. application Ser. No. 14/953,548.

Referring now to FIG. 6, placement of prosthetic tissue valve 10 aproximate a mitral valve region will be described in detail.

According to the invention, the valve 10 a is disposed proximate themitral valve region. The initial placement of the valve 10 a can beachieved by various conventional means, including limited access heartsurgery and percutaneous delivery.

The proximal end 14 of the valve 12 is then sutured to the valve annulus105. The valve leaflet extensions 22 a, 22 b are then attached directlyto the papillary muscles 119 a, 119 b.

It is contemplated that, following attachment of the valve leafletextensions 22 a, 22 b to the papillary muscles 119 a, 119 b, the valveleaflet extensions 22 a, 22 b fuse to the papillary muscles 119 a, 119 band, in some embodiments, the valve leaflet extensions 22 a, 22 bremodel and regenerate functioning native chordae tendineae.

As indicated above, when the prosthetic tissue valve 10 a (and valve 10b) comprises an ECM prosthetic tissue valve, it is also contemplatedthat the points at which the valve leaflet extensions 22 a, 22 b connectto the papillary muscles 119 a, 119 b and the proximal end 14 of thevalve 12 is attached to the valve annulus 105 will serve as points ofconstraint that direct the remodeling of the prosthetic tissue valve 10a (and valve 10 b) into valve tissue and/or valve structures, includingchordae tendineae, that are identical or substantially identical toproperly functioning native valve tissue and valve structures.

According to the invention, the valve leaflet extensions 22 a, 22 b andnoted placement and attachment thereof significantly enhances thestrength and, hence, structural integrity of the prosthetic tissuevalves 10 a, 10 b shown in FIGS. 2-5. The valve leaflet extensions 22 a,22 b and noted placement and attachment thereof also preserves thestructural integrity of the papillary muscles 119 a, 119 b.

The valve leaflet extensions 22 a, 22 b (and noted placement andattachment thereof) thus significantly reduces the risk of suturefailure and rupture of the prosthetic valve tissue proximate thepapillary muscles 119 a, 119 b. The valve leaflet extensions 22 a, 22 b(and noted placement and attachment thereof) also significantly reducethe risk of rupture of the papillary muscles 119 a, 119 b.

Referring now to FIGS. 7A and 7B, there is shown another embodiment of aprosthetic tissue valve of the invention (denoted “10 c”). Asillustrated in FIG. 7A, the prosthetic tissue valve 10 c comprises acontinuous conical shaped, single sheet member 30 having proximal anddistal ends 32, 34. According to the invention, the proximal end 32 ofthe valve 10 c is sized and configured to engage a valve annulus regionof a mammalian heart.

As further illustrated in FIG. 7A, the distal end 34 of the valve 10 cis closed and, thus, is configured to restrict fluid flow therethroughwhen the interstices 36 a-36 d (discussed below) are in closed positionand opened positions.

In some embodiments of the invention, the proximal end 32 of the valve10 c (and valves 10 d and 10 e, discussed below) has an outer diameterin the range of approximately 1.0 mm to 5 cm.

According to the invention, the conical shaped member 30 and, hence,prosthetic tissue valve 10 c can (and valves 10 d-10 e) comprise anylength. In some embodiments of the invention, prosthetic tissue valve 10c (and valves 10 d-10 e) has a length in the range of approximately 5 mmto 150 mm.

In some embodiments of the invention, the conical shaped member 30 and,hence, prosthetic tissue valve 10 c (and valves 10 d-10 e) has aproximal end diameter and length ratio in the range of 5:1 to 2:1.

As illustrated in FIGS. 7A and 7B, the prosthetic tissue valve 10 cfurther comprises a plurality of open regions (referred to hereinafteras “interstices”) 36 a-36 d that are preferably disposed linearly over aportion of the length of the member 30.

In a preferred embodiment of the invention, the conical shaped member 30is configured to expand during positive fluid flow through the member30, as shown in phantom and denoted 30′ in FIG. 7A, and contract duringnegative fluid flow through the member 30, e.g. regurgitating bloodflow.

In a preferred embodiment, the interstices 36 a-36 d are configured toopen during the noted expansion of the conical shaped member 30′(denoted 36 a′, 36 b′, 36 c′ and 36 d′), wherein the positive fluid flowis allowed to be transmitted through the interstices 36 a′, 36 b′, 36c′, 36 d′, and close during the noted contraction of the conical shapedmember 30 (denoted 36 a, 36 b, 36 c and 36 d), wherein the negativefluid flow through said member 30 is restricted, more preferably,abated.

In some embodiments of the invention, the interstices 36 a-36 d have alength that is in the range of approximately 10% to 98% of the overalllength of the conical shaped member 30.

In some embodiments, the width of the interstices 36 a-36 d is in therange of approximately 1 mm to 30 mm.

According to the invention, the interstices 36 a-36 d can have the samelength and width or different lengths and widths. In some embodiments ofthe invention, the interstices 36 a-36 d have the same length and width.

Referring now to FIG. 7C, there is shown another embodiment of theprosthetic tissue valve 10 c that is shown in FIG. 7A. As illustrated inFIG. 7C, the prosthetic tissue valve, now denoted 10 d, comprises amulti-layer or sheet (each sheet denoted “31”) conical shaped member 30having an annular ring 38 disposed between each sheet 31. According tothe invention, the annular ring is designed and configured to securelyengage the prosthetic tissue valve 10 d to a valve annulus (and, hence,cardiovascular tissue associated therewith).

According to the invention, the outer circumference of the annular ring38 can comprise various dimensions. In some embodiments of theinvention, the ratio of the circumference of the annular ring 38 to theoperative valve circumference of prosthetic tissue valve 10 c (andprosthetic tissue valves 10 d-10 h) is in the range of approximately 1:1to approximately 3:1.

Referring now to FIG. 7D, there is shown yet another embodiment of theprosthetic tissue valve 10 c that is shown in FIG. 7A. As illustrated inFIG. 7D, the prosthetic tissue valve, now denoted 10 e, furthercomprises a structural ring 40 that is disposed on the distal end 34 ofthe valve 10 e.

As indicated above, according to the invention, the annular ring 38and/or structural ring 40 can comprise various biocompatible materials,such as disclosed in Co-Pending U.S. application Ser. No. 14/953,548.

In some embodiments of the invention, the annular ring 38 and/orstructural ring 40 comprise a polymeric composition comprising one ofthe aforementioned biodegradable polymeric materials.

In some embodiments, the annular ring 38 and/or structural ring 40comprise poly(urethane urea).

In some embodiments, the annular ring 38 and/or structural ring 40comprise poly(glycerol sebacate) (PGS).

In some embodiments, the annular ring 38 and/or structural ring 40comprise an ECM composition comprising ECM derived from one of theaforementioned mammalian tissue sources.

Referring now to FIGS. 8A and 8B there is shown another embodiment of aprosthetic tissue valve of the invention, where FIG. 8A illustrates theprosthetic tissue valve, denoted 10 f, in a pre-formed configuration andFIG. 8B illustrates the prosthetic tissue valve 10 f in a formedconfiguration.

As illustrated in FIGS. 8A and 8B, in a preferred embodiment of theinvention, the prosthetic tissue valve 10 f comprises a base member 50comprising a proximal valve annulus engagement end 52 having acircumferential ribbon connection region 58, and a distal end 54. Thebase member 50 further comprises a plurality of ribbons 56 that areconnected to and extend from the ribbon connection region 58.

As further illustrated in FIGS. 8A and 8B, each of the plurality ofribbons 56 comprise proximal and distal ends 56 a, 56 b, and first andsecond edge regions 53 a, 53 b that extend from the circumferentialribbon connection region 58 to the distal ends 56 b of each of theribbons 56 and, hence, distal end 54 of the base member 50.

As illustrated in FIG. 8B, in some embodiments, the ribbons 56 of theformed valve 10 f taper to a substantially coincident point 55, whereinthe base member 50 has a substantially conical shape.

In a preferred embodiment of the invention, the distal ends 56 b of theribbons 56 are engaged to each other in a joined relationship, whereinfluid flow through the distal ends 56 b of the ribbons 56 and, hence,base member 50 is restricted.

In a preferred embodiment of the invention, the distal ends 56 b of theribbons 56 are engaged to each other in a joined relationship, whereinfluid flow through the distal ends 56 b of the ribbons 56 and, hence,base member 50 is restricted when the fluid modulating regions 59(discussed below) are in open and closed positions.

As further illustrated in FIG. 8B, the proximal ends 56 a of ribbons 56are positioned circumferentially about the circumferential ribbonconnection region 58 of the base member 50, wherein the first edgeregions 53 a and the second edge regions 53 b of the ribbons 56 arepositioned adjacent each other and form a plurality of fluid flowmodulating regions 59.

In a preferred embodiment of the invention, the base member 50 isconfigured to expand during positive fluid flow through the base member50, as shown in phantom and denoted 50′, and contract during negativefluid flow through the base member 50, e.g. regurgitating blood flow.

In a preferred embodiment, the fluid flow modulating regions 59 areconfigured to open during expansion of the base member 50′ (as shown inphantom and denoted 59′), i.e. the first and second edge regions 53 a,53 b separate, as shown in phantom and denoted 53 a′, 53 b′, wherein thepositive fluid flow is allowed to be transmitted through the fluid flowmodulating regions 59′, and close during the contraction of the basemember 50, wherein the negative fluid flow through base member 50 isrestricted, more preferably, abated.

According to the invention, the base member 50 can comprise any numberof ribbons 56. In some embodiments of the invention, the base member 50has four (4) equally spaced ribbons 56.

According to the invention, the proximal end 52 of the valve 10 f issimilarly sized and configured to engage an annular region of amammalian heart.

According to the invention, the proximal end 52 of the valve 10 f (andprosthetic tissue valves 10 g and 10 h, discussed below) can similarlycomprise a circumference, i.e. operative valve circumference, in therange of approximately 20 mm to 220 mm.

According to the invention, the prosthetic tissue valve 10 f (andprosthetic tissue valves 10 g and 10 h, discussed below) can alsocomprise any length. In some embodiments of the invention, theprosthetic tissue valve 10 f (and prosthetic tissue valves 10 g and 10h) has a length in the range of approximately 5 mm to 150 mm. In someembodiments of the invention, the prosthetic tissue valve 10 f (andprosthetic tissue valves 10 g and 10 h) has a length in the range ofapproximately 10 mm to 100 mm.

In some embodiments of the invention, prosthetic tissue valve 10 f (andvalves 10 g and 10 h) has a proximal end diameter and length ratio inthe range of 5:1 to 2:1.

Referring now to FIG. 8C, there is shown another embodiment of theprosthetic tissue valve 10 f that is shown in FIG. 8B. As illustrated inFIG. 8C, the prosthetic tissue valve, now denoted 10 g, comprises amulti-layer or sheet (each sheet denoted “57”) base member 50 having anannular ring 38 disposed between each sheet 57, which is similarlydesigned and configured to securely engage the prosthetic tissue valve10 g to a valve annulus (and, hence, cardiovascular tissue associatedtherewith).

Referring now to FIG. 8D, there is shown yet another aspect of theprosthetic tissue valve 10 f that is shown in FIG. 8B. As illustrated inFIG. 8D, the prosthetic tissue valve, now denoted 10 h, furthercomprises a structural ring 40 that is disposed on the distal end 54 ofthe valve 10 h.

According to the invention, the structural ring 40 is preferably sizedand configured to receive ribbons 56 therein in close proximity to eachother, as shown in FIG. 8D.

According to the invention, the proximal end of the prosthetic tissuevalves of the invention can be secured to a valve annulus by variousconventional means, such as suturing the proximal end (with or withoutan annular ring 38) directly to the valve annulus tissue.

In some embodiments of the invention, ribbons 56 of prosthetic valves 10f, 10 g and 10 h are connected via a constraining band that ispositioned between the proximal and distal ends 52, 54 of the valves 10f, 10 g, 10 h. According to the invention, the restraining band cancomprise the same material as the valve base member 50 or a differentmaterial.

In some embodiments of the invention, ribbons 56 of prosthetic valves 10f, 10 g and 10 h are restrained at a predetermined valve region, e.g.,mid-point, between the proximal and distal ends 52, 54 of the valves 10f, 10 g, 10 h via a supplemental structural ring.

In a preferred embodiment of the invention, the conical shaped member 30of prosthetic tissue valves 10 c-10 d and base member 50 (and, hence,ribbons 56) of prosthetic tissue valves 10 f-10 h comprise an ECMcomposition comprising acellular ECM from one of the aforementionedmammalian tissue sources.

In some embodiments of the invention, the mammalian tissue sourcecomprises small intestine submucosa (SIS).

In some embodiments, the mammalian tissue source comprises mesothelialtissue.

In some embodiments of the invention, the ECM composition and, hence,conical shaped member 30 of prosthetic tissue valves 10 c-10 d and basemember 50 (and, hence, ribbons 56) of prosthetic tissue valves 10 f-10 hfurther comprises at least one additional biologically active agent orcomposition, i.e. an agent that induces or modulates a physiological orbiological process, or cellular activity.

In some embodiment, the annular ring 38 and/or structural ring 40comprise at least one additional biologically active agent orcomposition.

According to the invention, suitable biologically active agents includeany of the aforementioned biologically active agents.

In some embodiments of the invention, the ECM composition and, hence,conical shaped member 30 of prosthetic tissue valves 10 c-10 d and basemember 50 (and, hence, ribbons 56) of prosthetic tissue valves 10 f-10 hinclude at least one pharmacological agent or composition (or drug),i.e. an agent or composition that is capable of producing a desiredbiological effect in vivo.

In some embodiment, the annular ring 38 and/or structural ring 40comprise at least one additional pharmacological agent or composition.

According to the invention, suitable pharmacological agents andcompositions include any of the aforementioned agents, including,without limitation, antibiotics, and anti-inflammatories.

In some embodiments of the invention, the conical shaped member 30 ofprosthetic tissue valves 10 c-10 d and base member 50 (and, hence,ribbons 56) of prosthetic tissue valves 10 f-10 h comprise an outercoating.

In some embodiments, the annular ring 38 and/or structural ring 40comprise an outer coating.

In some embodiments of the invention, the coating comprises an ECMcomposition comprising acellular ECM derived from one of theaforementioned mammalian tissue sources.

In some embodiments, the ECM composition further comprises at least oneof the aforementioned biologically active agents or compositions.

In some embodiments, the ECM composition further comprises at least oneof the aforementioned pharmacological agents or compositions.

In some embodiments of the invention, the coating comprises one of theaforementioned polymeric compositions.

Referring now to FIG. 9, placement of prosthetic tissue valve 10 d in amitral valve region will now be described in detail.

According to the invention, prior to placement of prosthetic tissue vale10 d (as well as valves 10 c and 10 e-10 h) in a mitral valve region,the mitral valve 102 and chordae tendinae 103 a, 103 b can be removed orretained. Thus, in some embodiments of the invention, the mitral valve102 and chordae tendinae 103 a, 103 b are retained. In some embodiments,the mitral valve 102 and chordae tendinae 103 a, 103 b are removed.

After the mitral valve annulus region 107 is prepared, and, if elected,the mitral valve 102 and chordae tendinae 103 a, 103 b are removed, theprosthetic tissue valve 10 d is disposed proximate the mitral valveannulus region 107.

According to the invention, the initial placement of the prosthetictissue valve 10 d (as well as tissue valves 10 a-10 c and 10 e-10 h,discussed below) can be achieved by various conventional means,including limited access heart surgery and percutaneous transatrial,i.e. through the left atrium, and transapical delivery.

After disposing the prosthetic tissue valve 10 d proximate the mitralvalve region 107, the proximal end 32 of the prosthetic tissue valve 10d is secured to the valve annulus 105.

Referring now to FIG. 10, placement of prosthetic tissue valve 10 h in amitral valve region will now be described in detail.

After the mitral valve annulus region 107 is prepared and, if elected,the mitral valve 102 and chordae tendinae 103 a, 103 b are removed, thevalve 10 h is similarly disposed proximate the mitral valve annulusregion 107. The proximal end 32 of the prosthetic tissue valve 10 h isthen secured to the valve annulus 105.

Placement of prosthetic tissue valves 10 f and 10 g in a mitral valveregion are similar to placement of prosthetic tissue valve 10 h.However, in some embodiments of the invention, the distal ends 54 of theribbons 56 proximate the coincident point 55 of prosthetic tissue valves10 f and 10 g are connected to the inner surface of the ventricle 106via at least one active fixation lead (not shown).

As illustrated in FIG. 11, in some embodiments of the invention, thedistal ends 56 b of ribbons 56 are threaded through the heart wall 101and attached on the outside of the heart 100 in a joined relationship,wherein fluid flow through the base member 50 at the distal ends 56 b ofthe ribbons 56 is restricted. In some embodiments, the distal ends 56 bof ribbons 56 are secured into the heart wall muscle via cork-screwmechanism 61.

Referring now to FIGS. 12-14, a further embodiment of a prosthetictissue valve of the invention, and method for forming same, will bedescribed.

As illustrated in FIG. 13, the prosthetic tissue valve 10 i comprises aplurality of elongated ribbon members 60 having proximal and distal ends62, 64, as shown in FIG. 12.

In a preferred embodiment of the invention, the ribbon members 60similarly comprise an ECM composition comprising acellular ECM derivedfrom one of the aforementioned mammalian tissue sources.

In some embodiments, the ECM composition further comprises at least oneof the aforementioned biologically active agents or compositions.

In some embodiments, the ECM composition further comprises at least oneof the aforementioned pharmacological agents or compositions.

According to the invention, the ribbon members 60 can comprise anylength and shape. In some embodiments, the ribbon members 60 preferablycomprise a tapered shape along the longitudinal axis, such asillustrated in FIG. 12.

The ribbon members 60 can also comprise various widths proximate theproximal end 62. In some embodiments of the invention, the width of theproximal end 62 of the ribbons is preferably in the range ofapproximately 5 mm to 2 cm.

As illustrated in FIGS. 13 and 14, after attachment to a valve annulusregion, the distal ends 64 of the ribbon members 60 are also preferablypositioned circumferentially proximate each other, i.e. a first edgeregion 65 of each ribbon member 60 being disposed proximate the opposingsecond edge region 67 of an adjoining ribbon member 60, wherein aplurality of fluid flow modulating regions 66 are formed.

According to the invention, the first and second edge regions 65, 67 ofthe ribbon members 60 can also overlap.

The distal ends 64 of the ribbon members 60 are also preferablypositioned proximate each other in a joined relationship, i.e. asubstantially coincident point, proximate the distal end 63 of theprosthetic tissue valve 10 i, wherein the valve 10 i comprises asubstantially conical shaped valve structure.

As further illustrated in FIG. 13, in some embodiments, the prosthetictissue valve 10 i further comprises structural ring 40 that is disposedon the distal end 63 of the valve 10 i. According to the invention, thestructural ring 40, in this instance, is preferably sized and configuredto receive the distal ends 64 of the ribbons 60 therein and maintain thedistal ends 64 of the ribbons 60 in the joined relationship.

In a preferred embodiment of the invention, the valve structure 70 isconfigured to transition from an expanded position when the proximalends of the ribbon members are engaged to a valve annulus region andreceive fluid flow therein, and the fluid flow exhibits a positive flowpressure, to a contracted position when the fluid flow exhibits anegative flow pressure.

In a preferred embodiment, the plurality of fluid flow modulating arealso configured to transition from an open position when the valvestructure 70 is in an expanded position, wherein the plurality of fluidflow modulating regions allow the fluid flow to be transmitted throughthe valve structure 70, to a closed position when the valve structure 70is in a contracted position, wherein the plurality of fluid flowmodulating regions restrict fluid flow through the valve structure 70.

According to the invention, in some embodiments of the invention,prosthetic tissue valve 10 i is formed as follows:

After the mitral valve annulus region 107 is prepared, and, if elected,the mitral valve 102 and chordae tendinae 103 a, 103 b are removed, theproximal ends 62 of a plurality of ribbon members 60 are attached to thevalve annulus 105 (see FIGS. 13 and 14).

As illustrated in FIG. 13, in some embodiments, the first edge region 65of each ribbon 60 is disposed proximate the opposing second edge region67 of an adjoining ribbon 60. In some embodiments, the proximal end 62of the ribbon members 60 overlap.

The distal ends 64 of the ribbons 60 are then positioned proximate eachother in a joined relationship proximate the distal end 63 of theprosthetic tissue valve 10 i.

In some embodiments of the invention, the distal ends 64 of the ribbons60 are connected to the inner surface of the ventricle 106 via at leastone active fixation lead (not shown).

In some embodiments of the invention, the ribbons 60 are threadedthrough the heart wall 101 and attached on the outside of the heart 100.

In some embodiments of the invention, a structural ring is attached tothe distal ends 64 of the ribbons 60, wherein the distal ends 64 of theribbons 60 are maintained in the joined relationship.

In some embodiments of the invention, the prosthetic tissue valves 10c-10 i described above further comprise a supplemental supportstructure. In some embodiments, the support structure comprises at leastone internal biocompatible support ring that is disposed between theproximal and distal end of the valve. In some embodiments, the supportstructure comprises a biocompatible multi-link stent structure.

In some embodiments of the invention, the prosthetic tissue valves 10c-10 i described above further comprise at least one internal pre-formedleaflet, such as disclosed in Applicant's U.S. Pat. Nos. 8,709,076,9,011,526, 8,257,434 and 7,998,196, which are incorporated by referenceherein.

As indicated above, it is contemplated that, when the prosthetic tissuevalves 10 c-10 i comprise an ECM composition comprising acellular ECM(i.e. ECM prosthetic tissue valves), upon placement of the ECMprosthetic tissue valves 10 c-10 i to a valve structure, e.g., valveannulus 105, modulated healing of the valve structure and connectingcardiovascular structure tissue will be effectuated.

It is further contemplated that, following placement of the ECMprosthetic tissue valves 10 c-10 i in a subject on a cardiovascularstructure (or structures) in a subject, the ECM prosthetic tissue valves10 c-10 i will become populated with cells from the subject that willgradually remodel the ECM into cardiovascular tissue and tissue (and,hence, valve) structures.

It is further contemplated that, following placement of the ECMprosthetic tissue valves 10 c-10 i in a subject on a cardiovascularstructure (or structures) in a subject, stem cells will migrate to theECM prosthetic tissue valves 10 c-10 i from the point(s) at which thevalves are attached to the cardiovascular structure, e.g., valveannulus, or structures, e.g., valve annulus and heart wall.

It is still further contemplated that the points at which the ECMprosthetic tissue valves 10 c-10 i are attached to a cardiovascularstructure (or structures) in a subject will serve as points ofconstraint that direct the remodeling of the ECM into cardiovasculartissue and valve structures that are identical or substantiallyidentical to properly functioning native cardiovascular tissue and valvestructures.

It is still further contemplated that, during circulation of epithelialand endothelial progenitor cells after placement of the ECM prosthetictissue valves 10 c-10 i on a cardiovascular structure (or structures),the surfaces of an ECM prosthetic tissue valves 10 c-10 i will rapidlybecome lined or covered with epithelial and/or endothelial progenitorcells.

As will readily be appreciated by one having ordinary skill in the art,the present invention provides numerous advantages compared to prior artprosthetic valves. Among the advantages are the following:

-   -   The provision of improved methods for securely attaching        prosthetic valves to cardiovascular structures and/or tissue;    -   The provision of prosthetic tissue valves having means for        secure, reliable, and consistently highly effective attachment        to cardiovascular structures and/or tissue;    -   The provision of improved prosthetic tissue valves and methods        for attaching same to cardiovascular structures and/or tissue        that maintain or enhance the structural integrity of the valve        when subjected to cardiac cycle induced stress;    -   The provision of improved prosthetic tissue valves and methods        for attaching same to cardiovascular structures and/or tissue        that preserve the structural integrity of the cardiovascular        structure(s) when attached thereto;    -   The provision of prosthetic tissue valves that induce modulated        healing, including host tissue proliferation, bioremodeling and        regeneration of new tissue and tissue structures with        site-specific structural and functional properties;    -   The provision of prosthetic tissue valves that induce adaptive        regeneration;    -   The provision of prosthetic tissue valves that are capable of        administering a pharmacological agent to host tissue and,        thereby produce a desired biological and/or therapeutic effect;    -   The provision prosthetic tissue valves that can be implanted        without removal of the native AV valve;    -   The provision prosthetic tissue valves that can be implanted        without a cardiopulmonary bypass apparatus;    -   The provision prosthetic tissue valves that can be positioned        proximate a valve annulus transvascularly; and    -   The provision prosthetic tissue valves that can be positioned        proximate a valve annulus transapically.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. As such, thesechanges and modifications are properly, equitably, and intended to be,within the full range of equivalence of the following claims.

What is claimed is:
 1. A prosthetic valve, comprising: a valve structurecomprising an extracellular matrix (ECM) composition, said ECMcomposition comprising acellular ECM from a mammalian tissue source,said valve structure further comprising proximal and distal ends, and aplurality of elongated ribbons that extend from said valve structureproximal end to said valve structure distal end, each of said pluralityof ribbon members comprising proximal and distal ends, a first edgeregion that extends from said proximal end to said distal end of saidplurality of ribbon members and a second edge region that extends fromsaid proximal end to said distal end of said plurality of ribbonmembers, said proximal ends of said plurality of ribbon members beingpositioned circumferentially at said valve structure proximal end,wherein a valve annulus engagement end of said valve structure isformed, said distal ends of said plurality of ribbon members beingpositioned proximate each other in a joined relationship at said valvestructure distal end, wherein said first edge regions of said pluralityof ribbon members are positioned adjacent said second edge regions ofsaid plurality of ribbon members and form a plurality of fluid flowmodulating regions between adjacent ribbon members of said plurality ofribbon members; and a structural ring configured to receive said distalends of said plurality of ribbon members therein, said structural ringbeing positioned on and engaged to said valve structure at said distalend thereof, wherein said structural ring maintains said distal ends ofsaid plurality of ribbon members in said joined relationship, said valvestructure being configured to transition from an expanded position whensaid valve annulus engagement end of said valve structure is engaged toa valve annulus region and receives fluid flow therein that exhibits apositive flow pressure, to a contracted position when said fluid flowexhibits a negative flow pressure, said plurality of fluid flowmodulating regions being configured to transition from an open positionwhen said valve structure is in said expanded position, wherein saidplurality of fluid flow modulating regions allow said fluid flow to betransmitted through said valve structure, to a closed position when saidvalve structure is in said contracted position, wherein said pluralityof fluid flow modulating regions restrict said fluid flow through saidvalve structure, said valve structure being further adapted to remodelinto cardiovascular tissue and native valve structures, and induceremodeling of damaged cardiovascular tissue and regeneration of newcardiovascular tissue and tissue structures with site-specificstructural and functional properties, when said valve annulus engagementend of said valve structure is engaged to a valve annulus.
 2. Theprosthetic valve of claim 1, wherein said mammalian tissue source isselected from the group consisting of small intestine submucosa (SIS),urinary bladder submucosa (UBS), urinary basement membrane (UBM), liverbasement membrane (LBM), stomach submucosa (SS), mesothelial tissue,placental tissue, omentum tissue, heart tissue and lung tissue.
 3. Theprosthetic valve of claim 1, wherein said ECM composition furthercomprises at least one exogenously added biologically active agent. 4.The prosthetic valve of claim 3, wherein said biologically active agentcomprises a cell selected from the group consisting of a human embryonicstem cell, fetal cardiomyocyte, myofibroblast, and mesenchymal stemcell.
 5. The prosthetic valve of claim 3, wherein said biologicallyactive agent comprises a growth factor selected from the groupconsisting of transforming growth factor-beta (TGF-β), fibroblast growthfactor-2 (FGF-2), and vascular epithelial growth factor (VEGF).
 6. Theprosthetic valve of claim 1, wherein said structural ring comprisespoly(urethane urea).